myeloid-derived suppressor cells in parasitic infections

Myeloid-derived suppressor cells in parasitic infections

Jo A. Van Ginderachter1,2, Alain Beschin1,2, Patrick De Baetselier1,2

and Geert Raes1,2

1 Laboratory of Cellular and Molecular Immunology, Department of Molecular and Cellular

Interactions, VIB, Brussels, Belgium2 Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels,

Belgium

Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immature

myeloid cells that share a common property of suppressing immune responses. Several

helminth and protozoan parasite species have developed efficient strategies to increase the

rate of medullary or extramedullary myelopoiesis and to induce the expansion and accu-

mulation of immature myeloid cells such as MDSC. In this review, we examine current

knowledge on the factors mediating enhanced myelopoiesis and MDSC induction and

recruitment during parasitic infections and how the MDSC phenotype and mechanism of

immune modulation and suppression depends on the factors they encounter within the host.

Finally, we place MDSC expansion in the context of the critical balance between parasite

elimination and pathogenicity to the host and suggest attractive avenues for future research.

Key words: Myeloid-derived suppressor cells . Myelopoiesis . Parasitic infection .

T-cell suppression

Introduction

Parasitic infections are notoriously associated with suppression of

immune responses. Populations of mature myeloid cells, such as

macrophages in various activation states, are capable of display-

ing immunosuppressive features, and as a result play important

roles in the critical balance between parasite elimination and

pathogenicity to host tissues [1–3]. Heterogeneous populations of

immature myeloid cells, characterized by the surface expression

of both Gr-1 and CD11b molecules in mice and a shared potent

immune-suppressing activity in vitro and in vivo, have been

recognized to arise as a conserved response to various insults,

including cancer, bacterial and parasitic infections. Collectively,

these cells have been termed myeloid-derived suppressor cells

(MDSC) [4].

A number of factors complicate the analysis of MDSC biology.

First, MDSC are a heterogeneous mixture of immature myeloid

cells that are in various intermediate stages of myeloid cell

differentiation (reflected by expression of various levels of

macrophage and DC markers such as F4/80 and CD11c, respec-

tively, as well as MHC class II, CD80/86) and murine MDSC

consist of different subpopulations with varying levels of reac-

tivity with the Gr-1 monoclonal antibody. This Gr-1 antibody

binds a common epitope on the Ly6G and Ly6C antigens [5].

Using antibodies specifically recognizing Ly6C or Ly6G, MDSC

have been shown to contain at least two main subfractions: the

CD11b1Gr-1hiLy6G1Ly6Clo MDSC that bear resemblance to

polymorphonuclear granulocytes and were thus termed poly-

morphonuclear-type MDSC (PMN-MDSC) and the CD11b1Gr-

1loLy6G�Ly6Chi MDSC with a monocytic morphology that were

called monocytic-type MDSC (MO-MDSC) [6–9]. It is important

to keep in mind that positive CD11b and Gr-1 staining is not

unique to MDSC and not all CD11b1Gr-11 cells are immuno-

suppressive [10, 11]. The population of CD11b1Gr-11 cells is

therefore not fully equivalent to MDSC, but also includes

mature neutrophils [5], inflammatory monocytes [12, 13] and

the so-called TNF/iNOS-producing DC [14, 15]. In fact, in a

model of inflammation induction using combined LPS1IFN-gCorrespondence: Dr. Jo A. Van Ginderachtere-mail: [email protected]

& 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu

DOI 10.1002/eji.201040911 Eur. J. Immunol. 2010. 40: 2976–2985Jo A. Van Ginderachter et al.2976

Rev

iew

administration, suppressive activity was recently shown to be

exerted by both the CD11bintGr-1hi PMN-MDSC population with

ring-shaped nuclei and the CD11bintGr-1lo MO-MDSC population

with myelomonocytic morphology, but not by the CD11bhiGr-1hi

mature polymorphonuclear neutrophils [9]. Although it is fairly

feasible to distinguish PMN-MDSC from mature neutrophils in a

side-by-side comparison based on the morphology and differ-

ences in the expression level of makers such as CD11b, distinction

between MO-MDSC and Gr-11 (Ly6Chi) inflammatory monocytes

is far more difficult. Recently, CD124 (IL-4Ra) was proposed as

an MDSC marker, but CD124 expression levels appear equally

high on naıve Ly6Chi monocytes and are not necessarily linked to

suppressive capacity in all tumor models [7, 16]. The hetero-

geneity and plasticity of MDSC and the lack of markers to opti-

mally distinguish MDSC from other, more mature myeloid cell

types, render T-cell anti-proliferative activity to be the ultimate

defining characteristic of MDSC.

Despite the above-mentioned limitations, the impact of MDSC

on immune responses has made MDSC the topic of intense

research. To date, most of the attention has been focused on

cancer-associated MDSC, whereas relatively few studies have

reported the activation, phenotype and especially the role of

MDSC during parasitic infections (Table 1). In this review, we

discuss current insights into the mechanisms of MDSC expansion,

activation and their effect on T-cell proliferation and cytokine

secretion during parasitic infections.

Increased rate of myelopoiesis duringparasitic infections

A first prerequisite for the expansion and accumulation of

immature myeloid cells, such as MDSC, is an increased rate of

medullary or extramedullary myelopoiesis (Fig. 1). Several

parasite species have developed efficient strategies to increase

myeloid cell generation. In the mouse bone marrow, the

intracellular protozoan parasite Leishmania donovani specifically

infects macrophage-like stromal cells, which results in enhanced

production of the hematopoietic growth factor GM-CSF by these

cells and subsequent increase in granulocyte/macrophage colony

formation (GM-CFU) [17]. Concomitantly, the splenic capacity

for extramedullary myelopoiesis is increased 20- to 30-fold at

later time points of L. donovani infection in susceptible BALB/c

mice, due to a combination of selective GM-CFU progenitor

expansion and their active proliferation [18]. Interestingly,

comparing L. major infection in susceptible BALB/c versus

resistant CBA mice, high splenic levels of the myelopoietic

growth factor IL-3 and IL-3-responsive cells are associated with

disease susceptibility [19], and correlate with significantly

increased numbers of CD11b1Ly6G�Ly6Chi monocytic and

CD11b1Ly6G1Ly6Cint granulocytic cells (i.e. CD11b1Gr-1int and

CD11b1Gr-1hi cells, respectively) – including many immature

cells with ring-shaped nucleus – in the spleen of BALB/c

mice [20, 21]. It is worth noting that a very similar expansion

of splenic CD11b1Gr-11 cells is noticeable in mice upon

infection with other protozoa, including Trypanosoma brucei

[15], T. cruzi [22] and Plasmodium chabaudi [23]. The latter

delivers further proof of the intricate mechanisms developed

by certain parasites to skew the hematopoietic system

toward myelopoiesis. Indeed, acute P. chabaudi malaria infection

leads to a transient depletion of myeloid–erythroid progenitors

and loss of common lymphoid progenitors, followed by the

emergence of a new population of infection-induced atypical

IL-7Ra1c-Kithi progenitors [24]. Though these progenitors have

lymphoid and myeloid potential, they have a strong bias toward

the generation of CD11b1Gr-11 myeloid cells in the bone

marrow and spleen upon in vivo transfer. In the case of

Plasmodium, the sustained increase in myelopoiesis is in favor

of the host as it results in a nonlethal infection (P. chabaudi,

P. yoelii 17x). On the contrary, lethal malaria parasites

(P. berghei) only transiently increase myelopoiesis, which then

returns to subnormal levels [25].

Modulating myelopoiesis is not the prerogative of protozoan

parasites. Indeed, the helminth Schistosoma mansoni was shown

to increase the number of bone marrow GM-CFU during the acute

infection phase – correlating with increased M-CSF (or CSF-1)

and IL-3 levels – which then return to normal levels during the

chronic phase [26, 27]. Interestingly, the extramedullary

Table 1. Examples of medically important parasites

Disease Parasite Parasite type Published evidence

for MDSC expansion

African trypanosomiasis (sleeping

sickness in humans and Nagana in livestock)

T. brucei and T. congolense Extracellular protozoan Not available

American trypanosomiasis (Chagas’ disease) T. cruzi Intracellular protozoan [21, 41]

Leishmaniasis Leishmania sp. Intracellular protozoan [13, 20, 42]

Toxoplasmosis To. gondii Intracellular protozoan [47]

Malaria Plasmodium sp. Intracellular protozoan [23]

Schistosomiasis (snail fever) Schistosoma sp. Trematode (flatworm) [40, 56, 57]

Taeniasis (intestinal infection with adult stage)

and cysticercosis (tissue infection with larval stage)

Taenia sp. Cestode (tapeworm) [52, 55]

Lymphatic filariasis B. malayi and others Nematode (roundworm) [53]

Eur. J. Immunol. 2010. 40: 2976–2985 HIGHLIGHTS 2977


myelopoiesis in spleen and liver gradually increases throughout

the course of infection [28]. An intriguing observation is the

presence of high levels of GM-CFU in the liver granulomas

(higher than in femurs) during the chronic infection phase, which

are locally supported by GM-CSF and cell membrane-associated

proteoglycans [26, 29, 30]. Hence, to sustain a high production of

A

B

C

Figure 1. Schematic overview of the induction, activation, recruitement and function of MDSC during parasitic infections. (A) Upon acuteinfection with parasites, the host immune system is confronted with large amounts of pathogen-associated molecular patterns, including TLRligands, leading to the activation of innate immune cells and the production of inflammatory cytokines such as IL-6 and IL-1. In combination withthe enhanced parasite-induced production of myelopoietic growth factors (such as GM-CSF, M-CSF, IL-3, etc.), which elicit an increased rate ofmedullary and extramedullary myelopoiesis, potent MDSC are induced. Both host factors (such as S100A9) and parasite-specific molecules (suchas cruzipain and phosphorylcholine) might contribute to the accumulation of these cells. Subsequently, MDSC are attracted to the infection site, atleast partly under the influence of parasite excretory/secretory products such as oligosaccharides. This early sequence of innate immune events isexpected to be relatively similar for protozoa and helminths. (B) Adaptive T-cell immunity is in the acute infection phase of protozoa, and to alesser extent also helminths, Th1 oriented. The Th1 cytokine IFN-g can participate in MDSC induction, but is especially important for theactivation of the MDSC suppressive potential by inducing the iNOS protein and high NO production (M1-like MDSC), that exerts anti-T-cellproliferative activity. The consequences of MDSC-mediated suppression during acute infection are a balancing act between host-destructive andhost-protective effects. MDSC might inhibit protective Th1 immunity, thereby potentially exacerbating disease, but on the other hand these cellsmight limit inflammation-associated immunopathogenicity and increase survival. (C) Helminths, but also some protozoa, gradually skew T-cellimmunity toward a polarized Th2 response during chronic infection, along with the appearance of M2-like MDSC. These MDSC can imprint a Th2profile on naıve T cells, suggesting these cells are not only merely immunosuppressors but also immunoregulators. Their suppressive capacitydepends on M2-associated molecules, such as arginase I and peroxisome proliferator-activated receptor-g (PPAR-g), and could again inhibitprotective Th2 immunity, but also prevent Th2-associated pathogenicity.

Eur. J. Immunol. 2010. 40: 2976–2985Jo A. Van Ginderachter et al.2978


myeloid cells, myelopoiesis is gradually translocated from the

bone marrow to the granulomas throughout the course of

S. mansoni infection.

Overall, increasing the rate of myelopoiesis appears to be a

host response common to many parasitic infections, suggesting

a functional significance in regulating parasite-induced

pathogenicity.

Factors mediating MDSC induction duringparasitic infections

The induction of MDSC is a combined effect of enhanced

myelopoiesis and inhibited differentiation toward mature

myeloid cells. In this context, an array of inflammatory

mediators, such as inflammatory cytokines, TLR ligands and

members of the S100 protein family, was shown to contribute to

an optimal MDSC expansion and activation. Both in mouse and in

human, exposing the appropriate precursors (bone marrow and

peripheral blood mononuclear cells, respectively) to a combina-

tion of a hematopoietic growth factor (GM-CSF) and inflamma-

tory cytokines (IL-6, IL-1b) most efficiently generates immature

myeloid cells with a strong T-cell suppressive capacity [31, 32].

Similarly, potent MDSC can be obtained in vitro and in vivo by a

combination of LPS and IFN-g, which blocks progenitor differ-

entiation toward DC [9]. In the same vein, MyD88-dependent

TLR signaling was demonstrated to play a direct role in MDSC

expansion during polymicrobial sepsis [33]. Finally, high S100A9

(also known as MRP14 or calgranulin B) expression in immature

myeloid cells inhibits their differentiation toward DC and is

instrumental for MDSC accumulation in vivo [34].

These data are particularly relevant in the context of parasitic

infections. Indeed, IL-1 and IL-6 have long been known to be

involved in the immune response to protozoan parasites and at least

for some species, the induction of these inflammatory cytokines was

shown to be TLR and MyD88 dependent [35, 36]. In combination

with the enhanced circulating levels of hematopoietic growth factors

(e.g. GM-CSF, M-CSF and IL-3) during many of these infections, as

discussed in the previous paragraph, this perhaps formulates an

ideal cytokine composition for the expansion and activation of

MDSC. As a matter of fact, a sepsis-like situation often occurs during

the acute phase of protozoan parasite infection, including infection

with Trypanosoma, Toxoplasma, Plasmodium and Leishmania

species, given the overwhelming presence of parasites/TLR ligands

and the ensuing massive inflammatory/Th1 (IFN-g) responses [37,

38]. It should be noted that helminth parasites, such as S. mansoni,

also trigger TLR/MyD88 signaling to induce an early Th1 response,

which is subsequently converted to a dominant Th2 response [39,

40]. Remarkably, CTL-suppressive CD11b1Gr-11MHC II�CD161

F4/80dull cells, consistent with the phenotype of MO-MDSC,

are expanded in the spleen throughout the chronic phase of

S. mansoni infection [41].

One of the few reports establishing the link between parasite-

induced inflammatory cytokines and MDSC expansion is reported

by Voronov et al. [21]. L. major infection in susceptible BALB/c

mice leads to a gradual accumulation of CD11b1Gr-11 cells in

the spleen, both of monocytic and of granulocytic origin,

although this accumulation is found to a lower extent in IL-1a�/�

and IL-1b�/�mice. Conversely, mice deficient in the IL-1 receptor

antagonist dramatically expand CD11b1Gr-11 cells, clearly

correlating IL-1 activity in infected animals to CD11b1Gr-11 cell

accumulation [21]. Some evidence also points to IFN-g as an

important MDSC-regulating cytokine during parasitic infection.

Eliciting the atypical Lin�IL-7Ra1c-Kithi progenitor of CD11b1

Gr-11 cells during acute P. chabaudi infection critically depends

on progenitor-intrinsic IFN-g-R1 signaling [24]. IFN-g-R1 is also

absolutely required for splenic MDSC expansion observed in

T. cruzi infection [22]. Intriguingly, a highly mannose glycosyl-

ated and strongly immunogenic T. cruzi antigen – cruzipain –

was demonstrated to trigger extramedullary myelopoiesis and

CD11b1Gr-11 cell expansion in the spleen, thereby being one of

the few parasite-specific molecules known, to date, to drive

MDSC expansion [42].

It has been shown in cancer models that MDSC accumulate

under the influence of the S100A9 protein and S100A91 cells were

detected in the spleen and within the tumor [34]. Interestingly,

older data link the susceptibility of mice to L. major infection with

the appearance of S100A91 cells in the lesion [43]. Although early

lesions in resistant C57BL/6 mice contain more leishmanicidal

mature macrophages, the lesions in susceptible BALB/c mice

are infiltrated more by S100A91 cells with the morphology

of undifferentiated monocytes and cells with ring-shaped

nuclei that are typical of MDSC [43]. Injecting resistant mice with

S100A91-enriched cells prolonged the course of infection and

increased local parasite spread. Conversely, reducing the infiltration

of S100A91 cells in susceptible mice decreased parasite load and

delayed progression of disease [44]. Along the same line, S100A91

small mononuclear cells significantly increased in different tissues

after S. mansoni infection in mice and concentrated in the liver

around dilated blood vessels and at the edge of granulomas.

Importantly, more differentiated macrophages in the center of

granulomas were S100A9-negative [45].

Besides employing host factors such as S100A9, parasites might

directly inhibit DC differentiation and maturation resulting in the

accumulation of immature myeloid cells. In vivo exposure of bone

marrow progenitors to the phosphorylcholine-containing filarial

nematode glycoprotein ES-62 prevents their in vitro differentiation

and maturation to inflammatory DC and macrophages, whereby

phosphorylcholine appears to be the active component [46].

Phosphorylcholine is a conserved structural component of a variety

of pathogens, including the protozoa L. major and T. cruzi and all

species of filarial nematodes examined so far, suggesting a common

mechanism shared between different parasites.

MDSC recruitment to tissues during parasiticinfections

In tumor-bearing mice, MDSC were shown to infiltrate the

primary tumor and locally undergo a partial differentiation



program, acquiring even stronger T-cell suppressive capacities

[47]. Hence, MDSC are subjected to a changing microenviron-

ment and might behave differently in distinct tissues. Similarly,

depending on the parasite, different organs can be afflicted by the

infection and different types of immune response are elicited, and

hence the questions of whether MDSC are recruited to infected

organs, whether MDSC are influenced by the environment and

whether they exert locally T-cell suppressive activity are of

relevance/interest in understanding the effects of parasitic

infection on the immune system.

Intragastric delivery of Toxoplasma gondii cysts to C57BL/6

mice leads to an acute infection in several organs, including the

lungs and the ileum. Infected lungs are massively infiltrated by

CD11b1Gr-11(CD11c�Mac3lo) monocytic cells, which are able to

suppress the proliferation of ConA-stimulated lymphocytes (thus

defining them as MDSC), but the mechanism of lung infiltration is

uncertain [48]. Importantly, using the same infection route,

monocytic CD11b1Gr-11 cells also home to the ileum, demon-

strating the active recruitment of these cells to distinct sites of

infection [49]. As a matter of fact, experimental To. gondii

infections in the peritoneal cavity recruits CD11b1Gr-11 cells to

that site, further concretizing the idea that MDSC are recruited to

sites of infection and exert their suppressive activity locally [50].

Though the ileal CD11b1Gr-11 cells were not tested for

suppressive activity, their absence leads to inflammatory tissue

destruction and ultimately death due to intestinal necrosis [49],

allowing the hypothesis that these cells are needed as direct

suppressors of inflammation. Indeed, although Th1 immunity is

required for killing of protozoa, the dark side of overt parasite-

induced inflammation could be immunopathogenicity, including

anemia, organ damage and eventually death. Hence, MDSC could

potentially be instrumental in fine-tuning the level of inflamma-

tion during early protozoan infection. Too few MDSC might lead

to inflammatory disease, whereas too many of these cells could

jeopardize a protective Th1 response.

In contrast to the predominant inflammatory/Th1 response

elicited by protozoa, helminths are known to be efficient Th2

inducers during chronic infection. Since myeloid cells are char-

acterized by a high plasticity in phenotype in response to the trig-

gers to which they are exposed and the immune environment in

which they are expanded and activated, a different type of MDSC

might be induced by helminths. Indeed, monocytic MDSC seem to

fit in the concept of classically activated (or M1) versus alternatively

activated (or M2) mononuclear phagocytes, which are induced by

Th1 versus Th2 cytokines, respectively, and are distinguished

by their molecular repertoire including the enzymes involved in

L-arginine metabolism (high iNOS/NO for M1; high arginase I for

M2) [51–54]. Though MO-MDSC and mature macrophages can

adopt similar activation states when exposed to the same polarizing

environment, they can be distinguished based on their Gr-1

expression levels (Gr-11 MO-MDSC versus Gr-1neg macrophages).

As a matter of fact, MO-MDSC were shown to be precursors for M2

macrophages in some cancer models [8, 55].

Intraperitoneal implantation of BALB/c mice with the cestode

Taenia crassiceps induces an early mixed Th1/Th2 response,

followed by dominant Th2 immunity. Remarkably, monocytic

CD11b1Gr-1low and granulocytic CD11b1Gr-1hi cells gradually

accumulated in the peritoneum throughout the entire infection,

and coexist there with mature Gr-1neg macrophages [56]. The

monocytic fraction initially exerted enhanced arginase activity and

NO secretion (mixed M1/M2 phenotype), and later on produced

even higher amounts of arginase and low levels of NO (M2),

mirroring the switch from Th1/Th2 to polarized Th2 immunity.

Importantly, during both phases monocytic CD11b1Gr-11 cells

retained T-cell suppressive capacity, clearly illustrating the adapt-

ability of MO-MDSC to the environment. IL-4 and IL-13 are not only

crucial for inducing the M2-like MO-MDSC profile, but also for

attracting these cells to the peritoneum during chronic infection

[56]. A similar situation might apply to intraperitoneal inoculation

of Brugia malayi helminths, where during chronic infection M2-

oriented F4/801 (Gr-1 expression was not tested) cells are

massively recruited and suppress T-cell proliferation [57]. Inter-

estingly, the induction of suppressive peritoneal cells can be

mimicked by repeated injection of excretory/secretory products of

B. malayi, but also of other helminths such as Nippostrongylus

brasiliensis and Toxocara canis [58]. Moreover, a study by Terrazas

and colleagues showed that inoculation of Ta. crassiceps glycans is

sufficient to rapidly recruit MO-MDSC in a IL-4/IL-13-independent

fashion, suggesting that this mechanism might be dominant in the

acute infection phase [59]. Similarly, two schistosome oligo-

saccharides, lacto-N-fucopentaose III and lacto-N-neotetraose, trig-

gered the rapid recruitment of suppressive CD11b1Gr-11F4/801

MO-MDSC to the peritoneum [60, 61]. Hence, helminths appear to

modulate the host response through parasite-expressed products,

including oligosaccharides.

Effects of parasite-induced MDSC on T-cellfunctions

MDSC suppress T-cell proliferation

MDSC are best known for their capacity to inhibit T-cell

proliferation through various mechanisms [62]. Considering the

variety of organs in which MDSC operate and the diversity of

immune signals to which they are exposed in the course of

distinct parasitic infections, the mechanism of suppression by

parasite-elicited MDSC may also vary.

L-arginine metabolism has long been implicated in the

suppressive activity of MDSC, but also of mature macrophages.

NO-mediated hyporesponsiveness of T cells is well documented

during the acute infection phase of protozoan parasites, such as

T. brucei [63], T. cruzi [64], P. chabaudi [65] and To. gondii [66],

but also of several worms [67, 68]. Only recently, CD11b1Gr-11

MDSC were shown to be the main NO producers during several of

these infections. Consequently, NO was shown to be the main

mediator of suppression by MDSC from To. gondii-infected lung

[48], T. cruzi-infected spleen [22] and schistosome carbohydrate-

inoculated peritoneum [60, 61]. In addition, IFN-g was proven to

be critical for the induction of the iNOS protein and the enhanced



production of NO by parasite-induced MDSC [22, 60, 61]. Hence,

the inflammatory and Th1-dominated immunity generated early

after protozoan, but to some extent also helminth, infection is

instrumental for the generation of NO-dependent myeloid

suppressors.

Should the infection, however, develop into the chronic

phase, the immune response might change and consequently also

the MDSC suppressive mechanism. The occurrence of different

suppressive mechanisms by myeloid cells in the spleen during

early (NO/IFN-g-dependent) and late (NO/IFN-g-independent)

stages of infection was documented for T. brucei [63] and

To. gondii [66, 69]. Similarly, during intraperitoneal infections

with the cestode Ta. crassiceps, CD11b1Gr-11 MDSC from early

stage-infected animals impaired T-cell proliferation solely by

secreting NO, despite the coexpression of arginase I in those cells

[56]. Yet, these MDSC lost their ability to secrete NO in the late

stage of infection, which was concomitant to their increased

arginase activity. At that point, their suppressive potential relied

on arginase activity, which facilitated the production of reactive

oxygen species, including H2O2 and superoxide, by an altered

iNOS enzymatic reaction, as described before for cancer-asso-

ciated MDSC [70]. In addition, the suppressive activity of these

alternatively activated MDSC also depended on 12/15-lipoxy-

genase activation generating lipid mediators, which triggered

peroxisome proliferator-activated receptor-g (PPAR-g) [56].

Interestingly, high arginase activity by monocytes/macrophages

and possibly MDSC suppresses both Th1-induced inflammatory

pathogenicity during acute schistosomiasis [71] and Th2-induced

chronic pathogenicity by suppressing Th2-cell expansion and

reducing liver fibrosis [72], extending the lifespan of these

animals. On the contrary, arginase-induced L-arginine depletion

in L. major lesions leads to local suppression of the protective Th1

response and a nonhealing phenotype [73].

Overall, it is clear that different types of MDSC can be induced

during different parasitic infections and that these cells might

influence the course of pathogenicity using mechanisms very

similar to what is seen for cancer-induced MDSC.

MDSC instruct the Th profile

T-cell proliferation and T-cell cytokine production are not

necessarily linked phenomena. Data with parasite-induced MDSC

indeed suggest that suppression of T-cell proliferation does not

preclude an instructive role of these cells on the Th cytokine

profile. MDSC from the acute Ta. crassiceps infection stage induce

both IFN-g and IL-4 secretion by cocultured mitogen-stimulated

naıve lymph node cells, despite inhibiting their proliferation [56].

The more alternatively activated MDSC from the chronically

infected peritoneum also stimulate IL-4, but not IFN-g production

[56], indicating that the activation state of MDSC determines

their potential in instructing T cells. As a matter of fact, B. malayi-

induced alternatively activated myeloid suppressors do not

induce anergy in CD41 T cells but rather imprint a Th2 profile

in these cells, as shown by their proliferative response and

polarized Th2 cytokine production upon secondary restimulation

in the absence of MDSC [57]. A similar experiment with the

schistosome oligosaccharide lacto-N-neotetraose-triggered

MDSC, also demonstrated their Th2-imprinting capacity [61].

Hence, MDSC might not merely be suppressors of all kinds of

responses, but actually function as immunoregulators during

parasitic infections.

Conclusions and perspectives

In contrast to the wealth of studies dealing with cancer-associated

MDSC, relatively few studies have reported the role of MDSC

during parasitic infections. Yet it is clear that enhanced

myelopoiesis and expansion of immature myeloid cells is a

common phenomenon during infections with a range of helminth

and protozoan parasites. A number of studies have reported that

the expanded cells actually exert anti-proliferative and immuno-

modulatory effects on T cells and thus can indeed be classified as

MDSC. As is common among myeloid cells, these MDSC exhibit

an inherent plasticity of maturation, differentiation and activa-

tion in response to the immune environment and pathogen-

derived triggers to which they are exposed. Hence, their

expansion, recruitment to organs, phenotype and mechanism of

suppression can vary depending on the range of host- and

parasite-derived factors they encounter. As a consequence, a side-

by-side comparison of parasite-induced with cancer-induced

MDSC is complicated by the diversity of MDSC phenotypes

elicited by different parasites, and to some extent also different

tumors [6]. Importantly, the questions about the actual in vivo

role of these MDSC during parasitic infections and the mechan-

isms employed to affect parasite elimination and/or host

pathogenicity have only begun to be addressed.

Suppression of immune responses can play a critical role in

the long-term persistence of parasites in the host, but also reduce

parasite-induced morbidity, as documented for Treg [74–77].

Since both MDSC and Treg expand during parasitic infections,

the relative contribution of these cell types to immune suppres-

sion remains to be determined. Considering that tumor-induced

MDSC have been shown to act as tolerogenic antigen-presenting

cells capable of antigen uptake and presentation to tumor-specific

Treg [78–80] and that in a murine hepatocarcinoma model, a

feedback loop between mast cells, MDSC-derived IL-17 and Treg

in the tumor microenvironment was recently documented [81], it

may actually be interesting to assess whether MDSC activation

and Treg-mediated immune suppression are also linked under

certain conditions during parasitic infection.

Similar to the immune suppression by Treg, one can also

anticipate that MDSC can, on the one hand, limit the ability to

control infection through efficient anti-parasite immune respon-

ses and on the other hand limit the significant tissue damage that

can arise as a consequence of potent and sometimes over-vigor-

ous effector responses. A number of recent reports on nonpar-

asitic infections where MDSC expansion and/or activity had been

altered have provided experimental evidence for that dual



potential of MDSC. For instance, in a model of polymicrobial

sepsis, production of the acute-phase proteins CXCL1/KC and

serum amyloid A by hepatocytes was shown to be required for

peripheral mobilization, accumulation and survival of MDSC,

which were critical for controlling systemic inflammation and

protection from sepsis-associated mortality [82]. Thus, it seems

that pro-inflammatory acute-phase proteins can, through an

effect on MDSC, also play a feedback inhibitory role in attenua-

tion of inflammation. On the other hand, during influenza A virus

infections, invariant NKT cells were shown to reduce the immu-

nosuppressive activity of MDSC. In the absence of iNKT cells,

increased expansion of MDSC and suppression of influenza A

virus-specific immune responses was shown to result in high viral

titer and increased mortality [83]. Hence, besides demonstrating

that MDSC activity can either provide beneficial or provide

detrimental effects to an infected host, these findings also suggest

some potentially interesting avenues for testing the interaction of

MDSC with other immune players such as acute-phase proteins or

iNKT cells during parasitic infections.

Concerning the mechanism of suppression, up to now, the

inhibitory activity of MDSC has been mainly attributed to

modulation of L-arginine amino acid metabolism through

production of arginase and iNOS. However, during cancer

progression, MDSC also block T-cell activation by sequestering

cystine and limiting the availability of cysteine, an essential

amino acid for T-cell activation and function [84]. Several amino

acids are now recognized as playing regulatory roles in enhan-

cing the immune response (e.g. glutamine, arginine, tryptophan,

cystine/cysteine, glutamate and branched-chain amino acids) or

as anti-inflammatory agents (e.g. histidine) [85]. Whether MDSC

affect cystine/cysteine, tryptophan and other amino acid meta-

bolisms and hereby modulate T-cell function during parasitic

disease remains to be addressed.

Overall, their immunosuppressive activity makes MDSC

potential targets for therapeutic intervention. But before

contemplating this in the context of parasitic infections, in-depth

research into the conditions under which MDSC activity provides

either beneficial or detrimental effects to an infected host needs

to be performed. Therefore, one has to take into account not only

the immunomodulatory properties of MDSC but also potential

other effects these cells may have. For instance, NO and arginase

have documented effects on viability of parasites such as Leish-

mania or trypanosomes [86, 87]. Thus, one cannot exclude that

MDSC may under certain conditions through L-arginine metabo-

lism not only suppress T-cell immunity but also have direct effects

on parasite viability. An important complication to such studies

results from the lack of specific markers to unambiguously

distinguish MDSC from closely related cells, in particular from

CD11b1Gr-1loLy6Chi inflammatory monocytes, which in recent

years were found to play protective or pathogenic roles during

various parasitic infections [15, 23, 49]. Finally, extending these

findings to parasitic infections in humans will be critical. Indeed,

although MDSC have been described to expand and associate

with clinical cancer stage and metastatic tumor burden in human

cancer patients [88], there is currently a lack of studies focusing

on MDSC expansion and activity during parasitic infections in

humans.

Acknowledgements: Work on MDSC in the authors’ laboratory

has been performed as part of an Interuniversity Attraction Pole

Program and was supported by grants from the ‘‘Institute for

Promotion of Innovation by Science and Technology in Flanders’’

(IWT-Vlaanderen), the ‘‘Fund for Scientific Research Flanders’’

(FWO-Vlaanderen) and the Foundation against Cancer (Stichting

Tegen Kanker).

Conflict of interest: The authors declare no financial or

commercial conflict of interest.

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Abbreviations: GM-CFU: granulocyte/macrophage colony formation �M1: classically activated mononuclear phagocytes � M2: alternatively

activated mononuclear phagocytes � MDSC: myeloid-derived

suppressor cells � MO-MDSC: monocytic-type MDSC � PMN-MDSC:

polymorphonuclear-type MDSC

Full correspondence: Dr. Jo A. Van Ginderachter, Department of

Molecular and Cellular Interactions, Laboratory of Cellular and

Molecular Immunology, VIB-Vrije Universiteit Brussel, Building E,

Level 8, Pleinlaan 2, B-1050 Brussels, Belgium

Fax:132-2-629-19-81

e-mail: [email protected]

Received: 6/8/2010

Accepted: 25/8/2010

Accepted article online: 21/09/2010



myeloid-derived suppressor cells in parasitic infections

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